I DESCRIPTION: (provided by applicant) Drugs such as cocaine and amphetamine, opioids and alcohol are chemically dissimilar and act directly at distinct cellular sites in the nervous system to elicit early signaling events. All these agents have the potential for substance abuse and addiction. Recent data suggests that the addictive effects of drugs and alcohol might converge on a common neural pathway and that glutamatergic signaling, particularly through the NMDA receptor is critical. Understanding the long-term changes induced by NMDA signaling could reveal molecular events critical for the processes of addiction. Additionally, cocaine and amphetamine abuse have been closely linked as risk factors in the occurrence of stroke. Currently there are few treatments for the debilitating effects of stroke on the brain. Identification of novel cell survival pathways could provide new therapeutic targets for the treatment of brain injury due to drug abuse or stroke. The following specific aims are proposed to investigate novel glutamate signaling pathways. Identification of NMDA and calcium dependent genes through Differential Analysis of primary Library Expression (DazLE). Functional characterization and cluster analysis of NMDA dependent genes. Identification of the subset of NMDA/calcium dependent genes that are regulated by NO and Ras/Erk dependent pathways. Characterization of the NMDA induced genes and candidate NMDA-dependent neuronal survival genes. Identification of the subset of NMDA-dependent genes that mediates cellular survival and plasticity. Short exposure of neurons to non-toxic concentrations of NMDA preconditions neurons against subsequent toxic NMDA exposure. This process is dependent on new protein translation and is a form of cellular plasticity. Genes will be identified that mediate neuronal survival.